Glaucoma is the second most common cause of blindness in the world. We have uncovered several basic steps in the pathogenesis of retinal ganglion cell (RGC) death in glaucoma, using experimental glaucoma in rats and eye bank human glaucoma eyes. Sequential steps in injury to RGC by glaucoma will be further elucidated, including participation of mechanosensitive channels (TRAAK) in RGC membranes, disturbance of the motor protein dynein that facilitates retrograde axonal transport, and specific deficits due to these injuries in neurotrophin delivery to RGC. Initial studies have detected a neuroprotective effect by the overexpression of brain-derived neurotrophic factor (BDNF) in RGC, and the studies proposed will further detail the benefit to RGC of the provision of BDNF, its receptor (trkB), and ciliary body-derived neurotrophic factor (CNTF). Internal events within RGC during injury and death will be examined, e.g. changes in early genes (especially c-jun) and cysteine proteases that produce events leading to apoptotic RGC death. Since there is more than one pathway to apoptosis, the potential involvement of apoptosis-inducing factor will be investigated, as well as the relative proportion of apoptotic to necrotic cell death. In order to determine if secondary degeneration plays a role in glaucoma, a model of partial optic nerve transection will be compared to the glaucoma model in rats to study specific similarities and differences among the 3 modes of cell death. For the first time, microarray technology will be applied to determining gene expression differences in the 3 disease models. The studies proposed here have already suggested several new avenues of non-intraocular pressure lowering therapy for glaucoma.